Fluconazole,.alpha.-(2,4-Difluorophenyl)-.alpha.-(1H-1,2,4,-triazole-l-ylme thyl)-1H-1,2,4-triazole-1-ethanol; 2,4-Difluoro-.alpha.-.alpha.-bis(1H-1,2,4-triazol-1-ylmethyl)benzyl alcohol; 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-propan-2-ol, is an antifungal agent and presents the following structure: ##STR2##
Canadian Letters Patent No. 1,170,263 [corresponding to U.S. Pat. No. 4,416,682 and European Patent Application Serial No. 0044605 (published Jan. 27, 1982)] purports to teach compounds having the following structure: ##STR3##
wherein y.sup.1 and y.sup.2 may be =N-, and R.sup.1 may be aryl (page 1, line 16) wherein aryl may be substituted by "halogen (e.g., fluorine, chlorine or bromine)" (page 2, lines 17-18) and processes for the manufacture thereof (see for example page 7, line 1 to page 9, line 21).
One of the molecules: ##STR4##
1,3-Bis-(1,2,4-triazol-l-yl)-2-2,4-dichloro-phenyl)-propan-2-ol is alleged to be teratongenic (alleged at page 3, line 17 of Canadian Letters Patent No. 1,181,076):
... foetuses from animals treated with the compound in which R=2,4-Dichlorophenyl at 20 mg/kg body weight showed malformations, in particular cleft palates. Examination of visceral and skeletal features revealed that this compound was teratogenic at doses as low as 1 mg/kg, e.g., presence of microphthalmia, increased incidence of dilation of the ureters and renal pelves, delay in ossification of some bones, and increased incidence of a 14.sup.th pair of ribs.
Also, the compound in which R=4-Chlorophenyl was extremely embryotoxic at 20 mg/kg, whilst the compound in which R=2-Chlorophenyl produced external abnormalities (cleft palate) at this dose. These compounds are specifically disclosed as "Compounds 1 and 9," respectively, in Table 1 of the ICI applications. In addition, the compounds in which R=3-Chlorophenyl and R=4-Bromophenyl, which are claimed but not specifically disclosed in the ICI applications, also produced the same external abnormalities at 20 mg/kg. The latter compounds was also embryotoxic at this dose (page 4, line 16- page 5, line 9).
It is clear that, if true, this useless compound is claimed to be one of the compounds of the purported invention of Canadian Letters Patent No. 1,170,263.
The said Canadian Letters Patent No. 1,170,263 and corresponding U.S. patent and European application referred to above disclose processes for the manufacture of Fluconazole, wherein R.sup.1 is aryl substituted by the halogen (fluorine) and Y.sup.1 and Y.sup.2 is =N-.
Canadian Letters Patent No. 1,181,076 discloses only Fluconazole and was actually filed in Canada on Jun. 4, 1982. European Patent Application Serial No. 0044605 (corresponding to Canadian letters Patent No. 1,170,263) was published 27.01.82. Canadian Letters Patent No. 1,181,076 discloses the same processes as does Canadian Letters Patent No. 1,170,263 and European Patent Application Serial No. 0044605.
Canadian Letters Patent No. 1,182,822 relates to an intermediate for making Fluconazole. Several methods for the synthesis of Fluconazole are reported in the literature (EP 0096569; ES 9002961; CA 1,191,076; CA 1,182.822; CA 1,170,263; ES 9502961; GB 2099818; US 4,404,216; ES 549020; ES 549684; ES 549022; ES 549021; EP 83-303244) and some prominent ones are listed below:
(a) The reaction of 1,2,4-Triazole with compound of formula II-B gives Fluconazole. Compound II was prepared according to the following scheme (Canadian Letters Patent No. 1,181,076): ##STR5##
This method involves conversion of epoxide (II-B) to Fluconazole (44% yield). Epoxide (II-B) was prepared from commercially-available 1,3-Difluorobenzene over three steps. Although the chemistry involved is not too difficult, the yields obtained in Steps 2-4 are very low. The overall yield in this process Difluororbenzene .fwdarw.Fluconazole is about 4-8%.
(b) Fluconazole is also obtained by reacting 1,2,4-Triazole with a compound of formula III-B, which in turn is prepared according to the following scheme. Alternatively, Compound I can be obtained by the reaction of 1,3-ditriazole acetone with the corresponding Grignard of Difluorobenzene (CA 1,182,822; CA 1,181,076; ES 549020). ##STR6##
In this process, 1-Bromo-2,4-difluorobenzene is converted to its corresponding 1-lithiated derivative or a Grignard. This intermediate is reacted with highly toxic and corrosive dihaloacetone to obtain the dihalo alcohol which is in turn converted to Fluconazole.
Lithiation of 1-Bromo-2,4-difluorobenzene involves the use of the highly sensitive (to moisture, air), highly flammable, and corrosive compound n-Butyl Lithium. Also, the solvents used in both lithiation and Grignard reactions are Diethyl Ether or Tetrahydrofuran. These solvents are extremely flammable and hazardous. The above-mentioned reagents and solvents are dangerous to handle in large quantities, and hence this method is not very attractive for largescale commercial production.
Compared to these two methods, Applicant's synthesis involves reaction conditions and reagent (raw materials) that are suitable for synthesis on a large scale. Better yields are obtained. The method achieves a total yield far greater than those percentages referred to previously (from the starting materials through the intermediates to the final product).
It is therefore an object of this invention to provide a new process for the manufacture of Fluconazole from starting materials which are readily available commercially, easily handled, relatively inexpensive, and relatively safe to use. The use of these starting materials produces such intermediates in high yields. Fluconazole is also produced in high yields. Thus, Fluconazole is produced by simple reactions in high yields, using commercially available inexpensive agents which are not hazardous.
It is therefore a further object of the invention to provide such processes which are more environmentally- and user-acceptable.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention and detailed description of embodiments thereof.